Ocular Melanoma
Conditions
Keywords
STA9090, STA-9090, HSP90
Brief summary
STA-9090, a synthetic small molecule, demonstrates significant activity for down-regulating Heat Shock Protein 90 or Hsp90 levels. Hsp90 belongs to a class of molecular chaperone proteins known to be critical regulators of cancer cell proliferation and survival. Preclinical laboratory experiments have shown STA-9090, an Hsp90 inhibitor, could inhibit ocular melanoma cell lines. The primary objective of this trial is to obtain evaluations of STA-9090 efficacy to metastatic ocular melanoma.
Detailed description
Patients with metastatic ocular melanoma have a poor prognosis and very limited standard therapeutic options. The recent discoveries of GNAQ and GNA11 mutations leading to MAPK pathway activation and the over-expression of c-Met generate the hypothesis that inhibition of hsp90 client proteins will provide clinical benefit. This study tests the feasibility and efficacy of hsp90 inhibition in patients with metastatic ocular melanoma. Multiple components of the MAPK pathway (B-Raf, C-Raf, cdk4) in addition to c-Met are client proteins of hsp90 and dependent of active hsp90 for stability. Inhibition of hsp90 should lead to decreased expression of these client proteins.
Interventions
DRUGSTA-9090
Sponsors
Beth Israel Deaconess Medical Center
Massachusetts General Hospital
Brigham and Women's Hospital
Synta Pharmaceuticals Corp.
Dana-Farber Cancer Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The original dose (Cohort A) was amended based on phase 1 data for safety. Therefore there are 2 separate arms reported.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed stage IV ocular melanoma * ECOG Performance status 0, 1, or 2 * 18 years of age or older * Laboratory values as indicated in the protocol * Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation * Presence of metastatic disease that would be amenable to the required biopsies * At least one site of measurable disease as defined by at least 1cm in greatest dimension. This site must be different from the sites to be used for biopsy. No prior radiation therapy or directed ablation to the site of measurable disease
Exclusion criteria
* Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier * Major surgery within 4 weeks prior to first dose of STA-9090 * Minor surgery within 7 days of first dose of STA-9090 * Embolization procedure or ablation procedure to treat tumor within 4 weeks of first dose * Participants may not be receiving any other investigational agents * Poor venous access for study drug administration unless patient can use silicone based catheters * History of brain metastases or of leptomeningeal involvement * History of allergic reactions or hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to STA-9090 * Baseline QTc \> 450 msec or previous history of QT prolongation while taking other medications * Ventricular ejection fraction (EF) of 55% or less at baseline * Treatment with chronic immunosuppressants * Melanoma of cutaneous, mucosal or acral-lentiginous origin or of unknown primary * Prior treatment with HSP90 inhibitor * Not willing to undergo biopsy before and after treatment * Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Other medications, or severe acute/chronic medical or psychiatric conditions or laboratory abnormality that may increase the risk associated with the study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the participant inappropriate for entry into the study * Pregnant or breastfeeding women * Individual with a history of a different malignancy are ineligible except for circumstances outlined in the protocol * HIV-positive individuals on combination antiretroviral therapy * History of or current coronary artery disease, myocardial infarction, angina pectoris, angioplasty or coronary bypass surgery * History of or current uncontrolled dysrhythmias, or requirement for antiarrhythmic medication, or Grade 2 or greater left bundle branch block * NYHA class II/III/IV congestive heart failure with a history of dyspnea, orthopnea or edema that requires current treatment with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers or diuretics * Current or prior radiation therapy to the left hemithorax
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 4-month Progression Free Survival (PFS) Rate | Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Relevant for this endpoint was status at 4 months. | 4-month PFS rate was defined as the proportion of participants alive, absent progression based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST) and on treatment at 4 months. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. |
| Expression of cMET | Estimated up to 24 hours after administration of STA-9090 | To estimate the proportion of patients with greater than 50% decrease in expression of HSP90 client protein c-MET 18-24 hours after administration of STA-9090 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Dz was evaluated every 8 weeks on treatment; Imaging was obtained as clinically indicated until off-study; Median (range) on-study duration (months) was cohort A: 8.7 (3.7 to 28.7) and cohort B: 4.5 (1.2 to 36.4 months). Thus, follow-up was up to 36.4m. | PFS based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Participants who did not experience progression were censored at date of last disease evaluation. |
| Objective Response Rate (ORR) | Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Median treatment duration was 1.8 months for each cohort [range: cohort A (0.9-12.5), cohort B (0.8-31.7)]. Thus, response on treatment was evaluated up to 31.7 months. | ORR is defined as achieving partial response (PR) or complete response (CR) based on RECIST 1.0 criteria on treatment. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. CR or PR status required confirmation no earlier than 4 weeks following first documentation. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. |
| Grade 3-4 Treatment-Related Toxicity Rate | AE assessment was ongoing from the start of study drug and up to day 30 post-treatment. Mean treatment duration was 1.8 months for each cohort [range: cohort A (0.9-12.5), cohort B (0.8-31.7)). Thus, AEs on treatment were followed up to 31.7 months. | All grade 3-4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted to calculate the proportion of participants experiencing at least one treatment-related grade 3 or 4 AE of any type on treatment. |
| Overall Survival (OS) | Survival follow-up occurred every 4 weeks long-term; Median (range) on-study duration (months) was cohort A: 8.7 (3.7 to 28.7) and cohort B: 4.5 (1.2 to 36.4 months).Thus, follow-up was up to 36.4m. | OS based on the Kaplan-Meier method is defined as the time from study entry to death or date last known alive. |
| Disease Control Rate (DCR) | Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Median treatment duration was 1.8 months for each cohort [range: cohort A (0.9-12.5), cohort B (0.8-31.7)].Thus, response on treatment was evaluated up to 31.7 months. | DCR is defined as achieving stable disease (SD), partial response (P R) or complete response (CR) based on RECIST 1.0 criteria on treatment. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. CR or PR status required confirmation no earlier than 4 weeks following first documentation. Progressive disease (PD) is at least a 20% increase in the sum LD of target lesions from smallest sum LD as reference or the appearance of one or more new lesions. Stable disease (SD) is neither meeting PR or PD. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. PR or better response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions. |
Countries
United States
Participant flow
Recruitment details
The first and last participants registered to cohort A on September 17, 2010 and June 6, 2011 and to cohort B on December 27, 2011 and May 12, 2014.
Participants by arm
| Arm | Count |
|---|---|
| STA-9090: Cohort A Cohort A participants received STA-9090 200 mg/m2 given intravenously (IV) over 1 hour once weekly (d1, 8, 15 of a 28 day cycle).
Participants were treated until evidence of disease progression, unacceptable toxicity, intercurrent illness or withdrawal. | 7 |
| STA-9090: Cohort B Cohort B participants received STA-9090 150 mg/m2 given intravenously over 1 hour (IV) twice weekly (d1, 4, 8, 11, 15, 18 of a 28 day cycle).
Participants were treated until evidence of disease progression, unacceptable toxicity, intercurrent illness or withdrawal. | 10 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Progressive Disease | 5 | 8 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | STA-9090: Cohort A | STA-9090: Cohort B | Total |
|---|---|---|---|
| Age, Continuous | 57.3 years STANDARD_DEVIATION 6.5 | 58.5 years STANDARD_DEVIATION 18.4 | 58.0 years STANDARD_DEVIATION 14.3 |
| Region of Enrollment United States | 7 Participants | 10 Participants | 17 Participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 7 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 10 |
| other Total, other adverse events | 7 / 7 | 10 / 10 |
| serious Total, serious adverse events | 2 / 7 | 9 / 10 |
Outcome results
Primary
4-month Progression Free Survival (PFS) Rate
4-month PFS rate was defined as the proportion of participants alive, absent progression based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST) and on treatment at 4 months. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Relevant for this endpoint was status at 4 months.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| STA-9090: Cohort A | 4-month Progression Free Survival (PFS) Rate | 0.059 proportion of participants |
| STA-9090: Cohort B | 4-month Progression Free Survival (PFS) Rate | 0.118 proportion of participants |
Primary
Expression of cMET
To estimate the proportion of patients with greater than 50% decrease in expression of HSP90 client protein c-MET 18-24 hours after administration of STA-9090
Time frame: Estimated up to 24 hours after administration of STA-9090
Population: There was a problem with the assay and therefore this endpoint was not measured.
Secondary
Disease Control Rate (DCR)
DCR is defined as achieving stable disease (SD), partial response (P R) or complete response (CR) based on RECIST 1.0 criteria on treatment. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. CR or PR status required confirmation no earlier than 4 weeks following first documentation. Progressive disease (PD) is at least a 20% increase in the sum LD of target lesions from smallest sum LD as reference or the appearance of one or more new lesions. Stable disease (SD) is neither meeting PR or PD. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. PR or better response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time frame: Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Median treatment duration was 1.8 months for each cohort [range: cohort A (0.9-12.5), cohort B (0.8-31.7)].Thus, response on treatment was evaluated up to 31.7 months.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| STA-9090: Cohort A | Disease Control Rate (DCR) | 0.286 proportion of participants |
| STA-9090: Cohort B | Disease Control Rate (DCR) | 0.30 proportion of participants |
Secondary
Grade 3-4 Treatment-Related Toxicity Rate
All grade 3-4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted to calculate the proportion of participants experiencing at least one treatment-related grade 3 or 4 AE of any type on treatment.
Time frame: AE assessment was ongoing from the start of study drug and up to day 30 post-treatment. Mean treatment duration was 1.8 months for each cohort [range: cohort A (0.9-12.5), cohort B (0.8-31.7)). Thus, AEs on treatment were followed up to 31.7 months.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| STA-9090: Cohort A | Grade 3-4 Treatment-Related Toxicity Rate | 0.143 proportion of participants |
| STA-9090: Cohort B | Grade 3-4 Treatment-Related Toxicity Rate | 0.80 proportion of participants |
Secondary
Objective Response Rate (ORR)
ORR is defined as achieving partial response (PR) or complete response (CR) based on RECIST 1.0 criteria on treatment. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. CR or PR status required confirmation no earlier than 4 weeks following first documentation. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time frame: Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Median treatment duration was 1.8 months for each cohort [range: cohort A (0.9-12.5), cohort B (0.8-31.7)]. Thus, response on treatment was evaluated up to 31.7 months.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| STA-9090: Cohort A | Objective Response Rate (ORR) | 0.0 proportion of participants |
| STA-9090: Cohort B | Objective Response Rate (ORR) | 0.10 proportion of participants |
Secondary
Overall Survival (OS)
OS based on the Kaplan-Meier method is defined as the time from study entry to death or date last known alive.
Time frame: Survival follow-up occurred every 4 weeks long-term; Median (range) on-study duration (months) was cohort A: 8.7 (3.7 to 28.7) and cohort B: 4.5 (1.2 to 36.4 months).Thus, follow-up was up to 36.4m.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| STA-9090: Cohort A | Overall Survival (OS) | 8.5 months |
| STA-9090: Cohort B | Overall Survival (OS) | 4.9 months |
Secondary
Progression-Free Survival (PFS)
PFS based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Participants who did not experience progression were censored at date of last disease evaluation.
Time frame: Dz was evaluated every 8 weeks on treatment; Imaging was obtained as clinically indicated until off-study; Median (range) on-study duration (months) was cohort A: 8.7 (3.7 to 28.7) and cohort B: 4.5 (1.2 to 36.4 months). Thus, follow-up was up to 36.4m.
Population: The analysis dataset is comprised of all enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| STA-9090: Cohort A | Progression-Free Survival (PFS) | 1.6 months |
| STA-9090: Cohort B | Progression-Free Survival (PFS) | 1.8 months |